This is the resubmission of a competitive renewal application;the grant has supported a successful and productive series of studies examining the clinical pharmacology of opioids. In the most recent funding period, studies examined buprenorphine and buprenorphine/naloxone under both single and repeated dose parameters in order to understand the pharmacological effects of this medication and its clinical use. In the previous competing renewal submission, there was high enthusiasm for much of the application, but minor concerns noted as well - primarily related to two different lines of proposed investigation (three studies of buprenorphine and three studies of methadone/naloxone), the level of innovation, and the calculation of sample sizes. In response to these concerns, this revision now focuses solely on studies of buprenorphine;it no longer includes studies of methadone/naloxone. It includes two new studies of a novel buprenorphine formulation - an intranasal product, thus adding further innovation to the application. And, a more detailed presentation of sample sizes for each study is now provided. Other reviewer comments are also addressed. The current application now proposes five human laboratory studies for the next period. Studies 1-3 are thematically linked through buprenorphine dose, and examine doses greater than 32 mg. They determine the dose-response curve for higher buprenorphine doses, the duration of buprenorphine's effects, and the blockade efficacy for higher doses. Studies 4 and 5 examine the acute opioid agonist effects of an intranasal buprenorphine formulation: in non-dependent opioid abusers, and in opioid maintained subjects undergoing experimentally induced opioid withdrawal. Specifically, the proposed five studies address the following questions: 1. In humans, can the descending limb of a bell-shaped dose-response curve be shown with buprenorphine? 2. What is the time course and characteristics of withdrawal following administration of a high dose of buprenorphine? 3. Can further improvements in blockade efficacy be achieved with high buprenorphine closes? 4. What is the abuse liability of different intranasal doses of buprenorphine in nondependent opioid abusers? 5. Does intranasal buprenorphine exert sufficient opioid agonist effect to suppress spontaneous opioid withdrawal? Results from these controlled human laboratory studies will provide information that is clinically informative about the use of buprenorphine, help to further characterize the pharmacologic effects of high doses of buprenorphine, and distinguish the profile of effects and degree of opioid agonist effects that can be achieved with a novel delivery form of buprenorphine.